The long-term goal of these studies is to understand how defects in maternal insulin transduction contribute to gestational diabetes mellitus (GDM) and the mechanisms leading to fetal macrosomia and obesity. Metabolic imprinting suggests the transmission of diabetic susceptibility genes from moth to offspring is less important than the maternal environment in producing second-generation insulin resistance, obesity, and diabetes. This proposal will use a series of established heterozygous transgenic mouse models will combined gene knockouts in the insulin receptor (IR/+), insulin receptor substrate-1 (IRS-1/+), and leptin receptor (db/+) genes to establish how genetic defects in insulin signaling and the hormones of pregnancy interact to provoke abnormalities in insulin signal transduction, beta-cell hypertrophy, and spontaneous hyperglycemia during pregnancy. Our studies will also determine how modifying maternal insulin resistance during pregnancy decreases hyperglycemia and the development of fetal macrosomia by studying db/+ mice that over-express the human GLUT4 gene. The association between maternal hyperglycemia and fetal genotype on fetal over/under growth and expression of insulin signaling proteins in liver and skeletal muscle will be determined during the perinatal period. The last goal will be to determine whether insulin resistance and obesity in early and later life is modified by inheritance of an abnormal genotype or the consequences of epigenetics (i.e. information that is heritable and alters the phenotype of offspring but is not encoded specifically in the genetic code of DNA. One of the immediate benefits of these models is that they provide information on the role of biochemical defects expressed against a constant genetic background, thus enabling us to observe epigenetic transmission of an altered metabolic phenotype originally induced by a genetic event (inheritance of the IR/IRS-1 or leptin receptor mutation). Because many metabolic disorders, such as diabetes, have both genetic and epigenetic components, this approach offers an opportunity to identify metabolic alterations that may be unique to genetic or epigenetic effects. The outcome of these studies will have important implications for the prevention and treatment of GDM.